Department of Cardiology, All India Institute of Medical Sciences, New Delhi

Last three decades have witnessed revolutionary changes in the management of patients with ST-elevation acute myocardial infarction (AMI). Despite the advances in pharmacological and interventional treatment, the magnitude of morbidity and mortality from AMI remains quite substantial. It is widely acknowledged that the key factor in the successful treatment of AMI by thrombolytic therapy is the time elapsed between the onset of symptoms and initiation of therapy. A meta-analysis of 22 trials, including more than 50000 patients, showed maximal effectiveness of thrombolytic therapy within the first hour of symptom onset (the golden hour), whereas the benefit was reduced by nearly 50% in the subsequent hour (the Boersma’s curve).¹ An estimated 65, 37, 26 and 29 lives are saved per 1000 patients when treated with thrombolytic therapy within 0-1, 1-2, 2-3 and 3-6 hours respectively.¹ If the patients of AMI can be identified and treated very early after the onset of symptoms, the infarction process can essentially be aborted.² Although these data have been recognized for nearly a decade, time-to-thrombolysis in major recent clinical trials still remains stalled at approximately 2.5 to 3 hours after the onset of symptoms.³

The obvious step in the continuing effort to shorten timeto-treatment and thus to achieve maximal myocardial salvage is the use of Prehospital-Thrombolysis. Although, this paradigm shift in the treatment of AMI to the prehospital setting rather than in the emergency department of a hospital sounds interesting, yet it raises several clinical, medico-legal and logistical issues.

Who Should Give Prehospital-Thrombolysis?

The European Task Force Report recommends that thrombolytic treatment should be administered by the first qualified person evaluating the patient whether this is before or after the hospital admission.⁷ Ideally a medical professional should administer thrombolytic therapy in the prehospital scenario. Due to technological advances in acquisition and transmission of 12-lead electrocardiogram to a referral center, initiation of thrombolysis by paramedic personnel is being increasingly employed.^8-12 A system of Prehospital-Thrombolysis delivered by paramedics with hospital-based decision and support via telemetry link has been found to be very effective.^8-12 However, paramedics must achieve an agreed competency in this regard. In many cases of suspected AMI where the diagnosis is uncertain or relative contraindications are present, physicians are required to exercise clinical judgment. Unlike physicians, paramedics should refrain from using thrombolytic therapy in these situations. They should follow relevant protocols and guidelines strictly.

Where to Initiate Prehospital-Thrombolysis?

Thrombolytic therapy was given on domiciliary basis (at home of the patient) by the general practitioner in the early trials of Prehospital-Thrombolysis.¹³ However, home setting is not equipped to handle complications related to the patient’s ischemic state, co-morbidities, or to reperfusion therapy. Further, valuable time is lost at home if rescue angioplasty is required. At present, Prehospital-Thrombolysis is advised to be initiated in a fully equipped ambulance of the emergency medical services (EMS) en-route to the hospital.

Choice of Agent for Prehospital-Thrombolysis

Various factors need to be considered regarding the choice of agent for prehospital thrombolytic therapy. These include ease of drug administration, its efficacy, potential for adverse reactions, cost, and storage. Streptokinase (first generation thrombolytic agent) is not an ideal option for a paramedic-initiated Prehospital-Thrombolysis. It has to be administered as an infusion and carries risk of allergic reactions and hypotension. Similarly, anistreplase (APSAC) though given as a bolus injection, has similar risks of allergic reactions. Alteplase [tissue-type plasminogen activator (t-PA), a second generation thrombolytic agent] has high safety and efficacy profile, but need for administration as an infusion makes it less attractive in the prehospital setting.

New third generation thrombolytic agents which are predominantly derivatives of alteplase include: reteplase (recombinant plasminogen activator, r-PA), tenecteplase (TNK-mutant of alteplase), and lanoteplase (novelplasminogen activator, n-PA).¹⁴ Reteplase has a great potential for prehospital administration. The advantages of this drug in the prehospital treatment are manifold. It is administered as a bolus injection. Since early reoccclusion of the infarct-related artery had been observed with single bolus administration, it is currently given as double boluses of 10 U each, 30 min apart. The drug-dosing pattern is standard irrespective of the body weight of the patient making its use simple in the prehospital scenario.¹⁵ An additional advantage of this drug may be its role in facilitating percutaneous-coronary intervention (PCI). Since the first bolus is given in the prehospital setting, the hospital staff has a choice of the treatment regime to follow; a second dose of reteplase or PCI once the patient arrives in the hospital. If the patient is still not in the hospital within 30 min, the other bolus can be given. This concept is being tested in the Pre-hospital Administration of Thrombolytic-Therapy with Urgent Culprit Artery Revascularization (PATCAR) pilot study. Presently, it appears that reteplase may be considered as the ‘drug of choice’ for prehospital administration. Another thrombolytic agent, tenecteplase, has relative long plasma half-life that allows for a single bolus application. Lanoteplase has plasma half-life 10 times that of alteplase and therefore can be administered as single bolus. But higher incidence of hemorrhagic stroke has been reported with this drug.¹⁴ Thus, the third generation thrombolytic agents are likely to replace current thrombolytic therapy regime in near future. Reteplase and tenecteplase are ideal agents to be used in setting of prehospital administration. However, a much higher cost and non-availability remain major issues in the developing countries.

Several randomized trials have compared the feasibility and efficacy of prehospital initiation of thrombolytic therapy with in-hospital treatment (Table 1).^2,13,16-21 Besides routine contraindications to thrombolytic therapy, patients having cardiogenic shock, altered consciousness, atrioventricular or bundle branch blocks, advanced age and symptoms of more than 6 hours duration have been excluded in majority of the trials of Prehospital-Thrombolysis. Individually, each of the trials favored Prehospital-Thrombolysis; but there was no statistically significant survival benefit. This dampened the initial enthusiasm for Prehospital-Thrombolysis. However, a meta-analysis of 6 major randomized trials involving more than 6,000 patients showed that time-totreatment from the onset of symptoms was reduced by 58 min with Prehospital-Thrombolysis (varying between 33 min in urban population to 130 min in rural population). This led to 17% relative risk reduction in the hospital mortality. The absolute risk reduction of 2% translated into one life saved for every 62 patients of AMI treated in the prehospital setting.¹⁶ Similarly, Boersma et al.¹ reported that one hour reduction in treatment time with prehospital initiation of thrombolysis resulted in benefit of 21 lives saved per 1000 patients treated within 3 hours from onset of symptoms (p=0.002).¹ These data resulted in resurrection of Prehospital-Thrombolysis and paved the way for testing newer, third generation thrombolytic agents.

Impact on Time Delay with Prehospital Administration of Newer Thrombolytics

The Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI)-19 trial tested the feasibility of bolus thrombolytic agent (reteplase) and evaluated the time saved by its prehospital administration.²² Prehospital initiation of thrombolysis resulted in time saving of 32 min (31 min prehospital v. 63 min in-hospital, p<0.0001). By 30 min after first medical contact, there was 10-fold increase in the proportion of patients receiving Prehospital-Thrombolysis (49% v. 5%, p<0.0001). At one hour, 97% patients received the prehospital reperfusion therapy in comparison to less than half in controls (p<0.0001).²² In a recently published study from a district hospital, tenecteplase took 10.5 min less time to prepare than standard treatment of streptokinase or t-PA (p<0.001).²³ Also, after the introduction of tenecteplase, the percentage of patients receiving thrombolysis within 30 min increased from 58% to 76% (p< 0.01).²³ This data may have significant implications for the practice of prehospital administration of this drug.

Impact of Adjuvant Therapy with Prehospital-Thrombolysis

Intravenous unfractionated heparin (UFH) either as bolus or bolus followed by infusion has been used as an adjuvant to thrombolytic therapy in prehospital setting.^24–26 The low molecular weight heparin (LMWH), being more convenient to use, seems more suitable for prehospital administration. Safety and efficacy of tenecteplase with LMWH, enoxaparin was earlier demonstrated in the in-hospital (ASSENT-3) trial.²⁵ The ASSENT-3 PLUS trial was designed to extend the same findings in the prehospital setting.²⁶ Though the primary efficacy end points tended to be lower with LMWH (14.2% v. 17.4%; p=0.08), there was increased risk of stroke (2.9% v. 1.3%, p=0.026) and intracranial hemorrhage (2.20% v. 0.97%, p=0.047) as compared to UFH. This occurred exclusively in the older population (>75 years). The increased risk for bleeding was augmented in the prehospital compared with in-hospital setting of earlier ASSENT-3 trial. Remarkably, UFH was safe in elderly patients in either prehospital or in-hospital settings.^25,26 So, pending results of future studies of dose modification of enoxaparin, only UFH is recommended as an adjunctive therapy to newer thrombolytics in the prehospital setting. 

Aborted Infarction- “The Ultimate Myocardial Salvage”

The expression “aborted infarction” was first used to describe the patients treated very early in the Myocardial Infarction and Triage Intervention (MITI) trial.² It was found that 40% of all patients treated within 3 hours of onset of symptoms had no evidence of infarction as measured by thallium scan at 30 days follow-up. Minimal infarct size of less than 10% was noted in additional 35% patients. The key factor influencing these results was the early treatment through prehospital triage and not necessarily prehospital administration of thrombolytic therapy. Few recent reports have focused on the impact of Prehospital-Thrombolysis on the incidence of aborted infarction.^27–29 Aborted infarction was defined on the basis of ECG criteria (subsiding of cumulative ST segment elevation and depression to <50% of the level at presentation), together with a rise of creatine kinase less than twice the upper limit of normal. As expected, the median time-to-treatment was shorter by approximately one hour in the prehospital group compared to in-hospital group (97 min v. 153 min, p<0.05). Prehospital-Thrombolysis was associated with a four-fold increase of aborted infarction compared with in-hospital therapy (17.1% v. 4.5%, p<0.05). Stepwise logistic regression analysis revealed that time-to-treatment of ≤ 2 hours was an important predictor of aborted infarction (p=0.005).²⁷ Thrombolysis within one hour of onset of symptoms was administered to 19% patients of prehospital group compared to only 3% in the in-hospital group. In comparison to established AMI, patients with aborted infarction had a significantly lower 30-day (1.0% v. 9.2%, p< 0.01) and 1-year mortality (2.2% v. 11.6%, p< 0.01).²⁷

Comparing Prehospital-Thrombolysis with Primary Percutaneous Coronary Interventions

Several meta-analyses of randomized trials have consistently shown the superiority of primary PCI over inhospital thrombolysis, even when it required transportation to other hospitals for PCI.^30,31 Since several trials have clearly shown gain in time-to-treatment with prehospital compared to in-hospital thrombolysis, it is logical to compare PCI with thrombolytic therapy in the prehospital setting. Comparison of Angioplasty and Prehospital-Thrombolysis In Acute-Myocardial Infarction (CAPTIM) trial randomized 840 patients presenting within 6 hours from onset of symptoms to either Prehospital-Thrombolysis with accelerated alteplase or primary angioplasty.²⁴ Despite the gain of an hour with Prehospital-Thrombolysis, there was no difference at 30 days in the primary composite triple end point of death, non-fatal MI, and non-fatal disabling stroke (8.2% for thrombolysis v. 6.2% for PCI, p=0.29).²⁴

A subgroup analysis of this trial determined the impact of time-to-treatment after onset of symptoms (<2 hours, early v. >2 hours, late) on the clinical outcomes in patients assigned to either Prehospital-Thrombolysis or primary PCI.³² Time-to-treatment after onset of symptoms was consistently shorter by an hour in the thrombolysis group than in the PCI group (difference of 55 min among patients randomized before 2 hours, p<0.0001 and of 63 min among patients randomized after 2 hours, p<0.0001). There was a strong trend toward lower 30-day mortality with Prehospital-Thrombolysis for patients randomized <2 hours from onset of symptoms (2.2% thrombolysis v. 5.7% PCI, p=0.058) whereas no difference in survival was seen in patients randomized later (5.9% v. 3.7% respectively, p=0.47).³² In other words losing one hour to implement a strategy of hospital transfer for primary PCI has a different impact on survival when patients are seen early as opposed being seen late. Also, in the <2 hours group, the incidence of cardiogenic shock was less frequent with thrombolysis (1.3% v. 5.3%, p=0.032), this was largely due to lower incidence of shock developing during transport to the hospital. Probably one hour delay imposed by primary PCI contributed to the development of cardiogenic shock in patients presenting early with their symptoms when maximum myocardial salvage is feasible. Beyond 2 hours, the rates of cardiogenic shock were very low, and similar in both the groups (0% with thrombolysis v. 0.5% with PCI).³² Thus, primary PCI fails to show superiority over thrombolysis in a small but important subgroup of patients who can receive thrombolysis within first two hours after the onset of symptoms.

Clearly, patients with contra-indication to thrombolytic therapy or in cardiogenic shock should be considered forprimary PCI. In situations where facility of PCI is not readily available (in rural or remote areas, or at odd hours of day) or where transit time is significantly higher, thrombolytic therapy at point of first medical contact (if feasible, prehospital) should be given. Based on the Boersma’s equation and its proposed modification,³³ the following rationale can be drawn.^34-40

(a) Patients presenting within 2 hours from onset of symptoms: These patients are the ideal candidates for prehospital administration of thrombolytic therapy. Primary PCI should be considered only if patient reaches hospital within this time frame without thrombolysis. However, a large registry data showed that only 8% of patients actually receive primary PCI within 2 hours of symptom onset due to combination of delays in patient presentation and those inherent to interventional strategy.⁴¹

(b) Patients presenting between 2–6 hours from the onset of symptoms: The effect of thrombolytic therapy weans off with time as the aging thrombi become more resistant to lysis. In comparison, primary PCI is far less timedependent in achieving reperfusion and salvaging ischemic myocardium. Given this superiority of PCI over thrombolytic therapy, patients presenting between 2–6 hours from the onset of symptoms should be considered for PCI even if it involves transfer to other hospital. The controversy of initiating thrombolysis for patients who are being shifted to other institutions for PCI is a subject of ongoing trials. Recent report from the National Cardiovascular Data Registry of American College of Cardiology highlighted the need of thrombolysis in patients who require transport to other institutions for PCI. Patients transferred on thrombolytic therapy had lower rate of mortality post-PCI (3.2% v. 5.8%, p<0.0001) perhaps due to lesser rate of occluded infarct-related artery prior to PCI (24.7% v. 49.2%, p<0.0001) in comparison to patients transferred without thrombolytic therapy.⁴² However, large scale randomized trials are needed to support this contention.

(c) Patients presenting beyond 6 hours from the onset of symptoms: Little myocardial salvage is expected beyond 6 hours, especially if the chest pain and ST segment elevation has settled. These patients have only modest benefit from thrombolytic therapy and are not candidates for Prehospital-Thrombolysis. These patients may be considered for coronary angiography and revascularization to achieve patent infarct-related coronary artery (open artery hypothesis), though the merits of this approach are still contentious.

The advantages of thrombolysis and primary PCI may be complementary and not mutually exclusive. In the CAPTIM trial all AMI patients (whether they received Prehospital-Thrombolysis or were destined for primary PCI) were shifted to a center with access to emergency or rescue angioplasty. About 70% of the patients treated by Prehospital-Thrombolysis underwent PCI up to day 30, and 33% had urgent PCI (26% labeled “rescue PCI” because of persistent ischemia).²⁴ Need for subsequent angioplasty in substantial number of cases seems to indicate that all patients receiving thrombolysis (prehospital or in-hospital) should undergo early elective angiography and, if required, coronary revascularization. However, there is no consensus on this approach at present, as the reported trials have given conflicting results. Few randomized trials have found facilitated angioplasty either inferior to or no better than primary PCI.⁴³ In contrast, some recent studies on thrombolytic therapy support this contention.⁴⁴ If future studies also support this concept, the management strategy for patients presenting early may change to prehospital administration of thrombolysis in ambulance (as this will even gain more time in these early hours) along with shifting the patient straight to tertiary care for elective or rescue angioplasty. The ongoing pilot study, PATCAR is specifically designed to address this issue in both the urban and rural population.

Prehospital-Thrombolysis: the Indian Context

The concept of Prehospital-Thrombolysis appears particularly relevant to India. The population is predominantly rural and patients have to travel long distances to avail medical facility. Even in the urban areas tertiary care centers are few in number and travel time may be long due to various factors including congestion. Although these circumstances seem to warrant an urgent need for Prehospital-Thrombolysis program, it will require tremendous infrastructure support. Nevertheless, future developments in this direction would be useful not only in achieving the maximum benefits of thrombolytic therapy to all patients of AMI but such networks will also serve as models of health care in the community.

References